CN101657462A - The Preparation Method And Their Intermediate of capecitabine - Google Patents

The Preparation Method And Their Intermediate of capecitabine Download PDF

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CN101657462A
CN101657462A CN200780052717.9A CN200780052717A CN101657462A CN 101657462 A CN101657462 A CN 101657462A CN 200780052717 A CN200780052717 A CN 200780052717A CN 101657462 A CN101657462 A CN 101657462A
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formula
benzene ring
reaction
derivative
deoxyfluorouracil
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CN101657462B (en
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蒋翔锐
欧洋
沈敬山
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Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical

Abstract

The present invention relates to the Preparation Method And Their Intermediate of capecitabine.The invention provides a kind of new capecitabine synthetic route, is that raw material has obtained capecitabine through three-step reaction with the deoxidation fluorouracil glucoside.The present invention also provides the intermediate of said synthesis route.This synthetic route is short, has avoided the generation of steric isomer, the yield height of method, and technological process is controlled easily, and product quality is stable.

Description

The Preparation Method And Their Intermediate of capecitabine
Capecitabine preparation method and intermediate technical field thereof
The invention relates to a preparation method of capecitabine and an intermediate thereof. Background
Capecitabine (Capec i tabine) is a prodrug of 5-fluorouracil, has selective effect on tumor cells, and can be used as an oral cytotoxic preparation.
Capecitabine itself is not cytotoxic, but can be converted into cytotoxic 5-fluorouracil in three steps under the action of in vivo enzymes. The concentration of enzymes associated with capecitabine metabolism in tumor tissues is higher than in normal tissues, thus making it selectively cytotoxic to tumor cells. It is composed of
The structural formula is as follows:。
the currently reported synthesis methods of capecitabine mainly comprise the following steps:
1. racemic triacetoxy ribofuranose is used to dock with 5-fluorocytosine, then reacted with acyl chloride to give an acylated product, which is hydrolyzed to give capecitabine (Bioorganic & medicinal ina l chemis try 8, 2000, 1697-
2. 5' -deoxy-5-fluoro-cytidine was used as starting material, which was subjected to two acylation steps and then hydrolyzed to give the product (Drug of the Future 21, 1996, 358-. Capecitabine
3. The hydroxyl and amino groups are acylated using pentoxyformyl chloride as acylating agent followed by selective hydrolysis to give the final product (US 005476932).
4. Using 5-fluorocytosine which has been acylated as a starting material, carrying out a docking reaction and then
End product (CN 166089).
Capecitabine
5. Using ribose as raw material, the final product (China; mu 4^ Ά Shi,. >15, 2005, 173) was obtained by transformation.
Capecitabine invention
The invention provides a new synthesis route of capecitabine, which takes deoxyfluorouracil as a raw material to prepare capecitabine.
The technical scheme of the invention is as follows:
the invention provides a compound, namely a deoxyfluorouracil derivative, which is shown as a formula (I):
(I) Wherein ^ is selected from a hydrogen atom, a straight chain or branched alkyl group containing 1-8 carbon atoms, a benzene ring or a substituted benzene ring; r2Can be selected from hydrogen atom, straight chain or branched chain alkyl containing 1-8 carbon atoms, benzene ring or substituted benzene ring.
The invention also provides a preparation method of the deoxyfluorouracil derivative shown in the formula (I), which comprises the step of carrying out condensation reaction on the deoxyfluorouracil and aldehyde or ketone in the presence of an acid catalyst to obtain the deoxyfluorouracil derivative shown in the formula (I).
The invention provides a compound, namely a deoxycytidine derivative, which is shown as a formula (II):
(Π), wherein ^ can be selected from hydrogen atom, alkyl, benzene ring or substituted benzene ring; r2Can be selected from hydrogen atom, alkyl, benzene ring or substitutedA benzene ring.
The invention also provides a preparation method of the deoxycytidine derivative shown in the formula (II), and the deoxycytidine derivative shown in the formula (II) is obtained by reacting the deoxyfluorouracil derivative shown in the formula (I) with phosphorus oxychloride, organic alkali and ammonia water. The invention provides a deoxycytidine derivative which is shown as a formula (in):
(III), wherein ^ can be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring; r2Can be selected from hydrogen atom, alkyl, benzene ring or substituted benzene ring.
The invention also provides a preparation method of the deoxycytidine derivative shown as the formula (in), and the method is used for reacting the deoxycytidine derivative shown as the formula (II) with a compound shown as the formula (IV) to obtain the deoxycytidine derivative shown as the formula (III).
(IV), R is a leaving group. Formula (IV)
The following three types:
the invention also provides a preparation method of capecitabine, which is characterized in that hydroxyl protecting groups of the deoxycytidine derivatives shown in the formula (in) are removed under an acidic condition to obtain the capecitabine.
The deoxycytidine derivative shown in the formula (III) is obtained by reacting a deoxycytidine derivative shown in the formula (II) with a compound shown in the formula (IV).
The deoxycytidine derivative shown in the formula (II) is obtained by reacting the deoxyfluorouracil derivative shown in the formula (I) with phosphorus oxychloride, organic base and ammonia water.
The deoxyfluorouracil derivative shown in the formula (I) is obtained by carrying out condensation reaction on deoxyfluorouracil and aldehyde or ketone in the presence of an acid catalyst. The method comprises the following specific steps:
III
the preparation method comprises the steps of carrying out condensation reaction on deoxyfluorouracil and different aldehydes or ketones to obtain a deoxyfluorouracil derivative shown in a formula (I), then carrying out reaction on the deoxyfluorouracil derivative with phosphorus oxychloride, organic alkali and ammonia water to obtain a deoxyfluorocytidine derivative shown in a formula (II), carrying out acylation reaction on the deoxyfluorouracil derivative with an acylation reagent shown in a formula (IV) to obtain the deoxyfluorocytidine derivative shown in the formula (III), and finally removing a hydroxyl protecting group under an acidic condition to obtain capecitabine.
In the above reaction, the condensation reaction of the deoxyfluorouracil with the aldehyde or ketone may be carried out in one or a mixture of toluene, benzene, acetone, tetrahydrofuran, dichloromethane, or dichloroethane to which an acidic catalyst is added. The acidic catalyst may be selected from p-toluenesulfonic acid, zinc chloride, tin chloride. The reaction temperature can vary within wide limits and is generally from-2 { rC to 120 ℃, preferably from 80 ℃ to 120 ℃, with the molar ratio of deoxyfluorouracil to aldehyde or ketone being from 1:1 to 1: 2.
The reaction of the deoxyfluorouracil derivative shown in the formula (I) with phosphorus oxychloride, organic base and ammonia water can be carried out in acetonitrile or other aprotic solvent mixed solvents mutually soluble with water. The reaction temperature is-io ℃ C-
At 30 ℃ and preferably at-5 ℃ to 20 ℃.
The deoxycytidine derivative represented by the formula (II) and the acylating agent represented by the formula (IV) may be carried out in acetonitrile or other aprotic solvent to which a basic catalyst is added. The basic catalyst can be inorganic base or organic base, and can be selected from potassium carbonate, triethylamine and pyridine. The reaction temperature is-io ℃ C-
50 ℃, preferably at 0 ℃ to 20 ℃. The mole ratio of the deoxycytidine derivative shown in the formula (II) to the acylating agent shown in the formula (IV) is 1:1.1-1:3, and preferably 1:1.1-1: 2.
The reaction for removing the protecting group from the deoxycytidine derivative represented by the formula (III) to obtain capecitabine can be carried out in an aqueous solution of a protonic acid, an alcohol solution or an ether solution of a protonic acid, or a solution of an aprotic acid. Preferably in alcoholic solutions of protic acids.
The invention realizes the following technical effects:
according to the method, deoxyfluorouracil with a determined configuration is used as a raw material, capecitabine is obtained through three steps of reactions, the synthetic route is short, and the generation of stereoisomers is avoided. The test proves that the method has high yield, easily controlled process and stable product quality. The specific implementation method comprises the following steps:
the present invention is further illustrated by the following examples, which are intended to more specifically illustrate preferred embodiments of the present invention and are not intended to limit the technical aspects of the present invention. The technical scheme of the invention is the technical scheme capable of achieving the purpose of the invention. That is, the following embodiments adopt temperature and reagent, which can be replaced by the above-mentioned corresponding temperature and reagent to achieve the objective of the present invention.
Dissolving 0.26 g (1.5 mmol) of p-toluenesulfonic acid in 20ml of acetone, adding 3.69 g (15mmol) of deoxyfluorouracil, stirring at room temperature for 24 hours, adding solid potassium carbonate into the reaction system, adjusting the pH value to 7, filtering, concentrating the filtrate to remove acetone to obtain a white solid, adding dichloromethane to dissolve the white solid, washing with water, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 3.83 g of a white solid (la) with the yield of 89.2%. la NMR (300 MHz, CDC13): δ 7.36 (d, 1H, J=7.6 Hz) , 5.67 (s, 1H), 4.67 (dd, 1H, J=8.0, 3.2 Hz) , 4.50 (dd, 1H, J=4.5, 3.6 Hz), 4.24 (m, 1H), 1.56 (s, 3H), 1.40 (d, 3H, J=6.3 Hz), 1.34 (s, 3H)； ESI— MS m/z (Μ+Γ) 287。
Dissolving 0.2 g (1.511111101) of zinc chloride in 201111 of acetone, adding 3.69 g (15mmol) of deoxyfluorouracil, stirring at-20 ℃ for 24 hours, adding potassium carbonate into the reaction system, adjusting the pH value to 7, filtering, concentrating the filtrate to remove acetone to obtain a white solid, adding dichloromethane to dissolve the white solid, washing with water, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a white solid Ia.
Dissolving 0.35 g (2 mmol) of p-toluenesulfonic acid in 100ml of toluene, adding 4.92 g (20 mmol) of deoxyfluorouracil and 6.87 g (65.0 mmol) of benzaldehyde for refluxing, stirring for 4 hours, cooling, filtering, taking 2.48 g of filter residue as a raw material, concentrating the filtrate, recrystallizing the residue with ethyl acetate and n-hexane to obtain 2.80 g of solid (lb) with the yield of 91.0%. lb NMR (300 MHz, CDC 1)3): δ 9.17 (s, 1H), 7.32-7.50 (m, 6H) , 6.09 (s, 1H), 5.74 (d, 1H, J=2.7 Hz), 4.96 (dd, 1H, J=3.0, 3.9 Hz) , 4.69 (m, 1H), 4.30 (m, 1H), 1.47 (d, 3H, J=6.3 Hz); EI -MS m/z (Μ+Γ) 334。
0.2 g (1.2 mmol) of p-toluenesulfonic acid was dissolved in 40ml of toluene, 3.0 g (12.2 mmol) of deoxyfluorouracil and 2.01 g (14.3 mmol) of m-chlorobenzaldehyde were added, refluxed for 4 hours, cooled, filtered, the residue was 0.7 g of the raw material, the filtrate was concentrated, and the residue was recrystallized with ethyl acetate and n-hexane to obtain 3.15 g of a solid (Ic) with a yield of 91.0%. Ic ` HNMR (300 MHz, CDC 1)3): δ 9.17 (s, 1H), 7.32-7.50 (m, 6H) , 6.09 (s, 1H), 5.74 (d, 1H, J=2.7 Hz), 4.96 (dd, 1H, J=3.0, 3.9 Hz) , 4.69 (m, 1H), 4.30 (m, 1H), 1.47 (d, 3H, J=6.3 Hz); EI -MS m/z (Μ+Γ) 368。
0.2 g (1.2 mmol) of p-toluenesulfonic acid was dissolved in 40 acetonitrile, 3.0 g (12.2 mmol) of deoxyfluorouracil and 3.26 g (14.3 mmol) of dimethoxydiphenylmethane were added, refluxed, stirred for 4 hours, cooled, filtered, the filtrate was concentrated, and the residue was recrystallized with ethyl acetate and n-hexane to give 2.3 g of solid (Id) with a yield of 46.0%. Id ^ NMR (300 MHz, CDC 1)3) δ 9.22 (brs, 1H), 7.31-7.52 (m, 6H), 5.82 (d, 1H, J =2.1 Hz), 4.88 (dd, 1H, J =6.9, 2.4 Hz), 4.55 (dd, 1H, J =6.6, 4.2 Hz), 4.42 (dd, 1H, J =6.6, 4.5 Hz), 1.42 (d, 3H, J =6.6 Hz); EI-MS M/z (M +) 410. Example 6:
Ma
dissolving 3.83 g (13.4 mmol) of la in 35 ml of anhydrous acetonitrile, adding 3.17 g (40.0 mmol) of pyridine and 4.88 g (40.0 mmol) of N, N-dimethylaminopyridine, cooling to 0 ℃, dropwise adding 6.14 g (40.0 mmol) of phosphorus oxychloride, stirring for 6 hours, pouring the reaction liquid into 0 ℃ ammonia water, stirring for 0.5 hour, separating, washing the organic phase with dichloromethane, combining the organic phases, drying the anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 6.0 g of crude product (IIa). Ila::H NMR (300 MHz, CDC13): δ 7.42 (d, 1H, J=5.7 Hz) , 5.57 (d, 1H, J=l.2 Hz) , 4.93 (dd, 1H, J=6.6, 1.8 Hz), 4.49 (dd, 1H, J=6.6, 1.5 Hz), 4.27 (dd, 1H, J=6.3, 4.2 Hz), 1.55 (s, 3H), 1.38 (d, 1H, J=6.6 Hz), 1.32 (s, 3H) ; EI— MS m/z (M+) 285。
example 7:
dissolving 3.83 g (13.4 mmol) of la in 35 ml of anhydrous acetonitrile, adding 3.17 g (40.0 mmol) of pyridine and 4.88 g (40.0 mmol) of N, N-dimethylaminopyridine at 30 ℃, dropwise adding 6.14 g (40.0 mmol) of phosphorus oxychloride, stirring for 6 hours, pouring the reaction liquid into 0 ℃ ammonia water, stirring for 0.5 hour, separating liquid, washing the organic phase with dichloromethane, combining the organic phases, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 6.0 g of crude product (Ila).
Examples 8 to 10:
compounds IIb, lie and IId were obtained in the same manner as in example 7 using Ib, Ic or Id, respectively, as starting materials.
lib: NMR (300 MHz, CDC13): δ 8.00 (d, 1H, J=8.6 Hz), 7.40-7.54 (m, 5H) , 6.11 (s, 1H), 5.88 (d, 1H, J=4.4 Hz), 4.94 (dd, 1H, J=8.8, 4.0 Hz), 4.69 (m, 1H), 4.20 (m, 1H), 1.36 (d, 3H, J=7.6 Hz); EI -MS m/z (M+) 333。
lie: EI -MS m/z (M+) 367。
lid: NMR (300 MHz, CDC13): δ 8.00 (d, 1H, J=8.6 Hz), 7.26-7.52 (m, 10H), 6.11 (s, 1H) , 5.73 (d, 1H, J=2.4 Hz), 4.96 (dd, 1H, J=6.8, 2.4 Hz), 4.59 (dd, 1H, J=6.6, 4.2 Hz), 4.46 (m, 1H), 1.42 (d, 3H, J=6.6 Hz). ESI- MS m/z (M+Na+) 432。
Example 11:
dissolving 6.0 g of Ila in 40ml of acetonitrile, adding 7.6 g (26.8 mmol) of N-pentyloxycarbonyloxytsuccinimide and 3.7 g (26.8 mmol) of potassium carbonate, stirring at room temperature for 24 hours, filtering, removing the solvent under reduced pressure, dissolving the residue in dichloromethane, washing twice with 1N hydrochloric acid, washing once with saturated brine, drying over anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain a residue, and performing column chromatography to obtain 3.43 g of a product (Ilia), wherein the yield in the two steps is 64%. Ilia NMR (300 MHz, CDC 1)3): δ 12.05 (brs, 1H), 7.41 (d, 1H, J=4.8 Hz), 5.65 (s, 1H), 4.87 (d, 1H, J=5.4 Hz), 4.49 (dd, 1H, J=4.2, 6.3 Hz), 4.14-4.28 (m, 1H), 1.70 (m, 2H), 1.56 (s, 3H), 1.28— 1.42 (m, 11H, J=6.3 Hz), 0.89 (t, 3H, J=7.2 Hz); ESI- MS m/z (M+Na+) 422。
Example 12 Ila (6.0 g) was dissolved in acetonitrile (40 ml), and 6.78 g (26.8 mmol) of m-nitrophenyl N-pentylcarbonate and 3.7 g (26.8 ol) of potassium carbonate were added, and the mixture was stirred at room temperature for 24 hours, followed by filtration, removal of the solvent under reduced pressure, dissolution of the residue in methylene chloride, washing twice with 1N hydrochloric acid, washing once with saturated brine, drying over anhydrous sodium sulfate, removal of the solvent under reduced pressure to give a residue, and column chromatography to give 3.33 g of the product (Ilia), with a yield of 62% in two steps.
Example 13:
dissolving 6.0 g of Ila in 40ml of acetonitrile, adding 4.02 g (26.8 mmol) of N-amyl chloroformate and 2.1 g (26.8 ol) of potassium carbonate, stirring at 0 ℃ for 2 hours, removing the solvent under reduced pressure, dissolving the residue in dichloromethane, washing twice with 1N hydrochloric acid, washing once with saturated saline, drying over anhydrous sodium sulfate, removing the solvent under reduced pressure to obtain a residue, and performing column chromatography to obtain 3.63 g of a product (Ilia), wherein the yield in two steps is 66%.
Ila Ilia
Examples 14 to 16:
using lib and lie as starting materials, compounds IIIb, IIIc and IIId were obtained in the same manner as in example 11.
Illb: NMR (300 MHz, CDC13): δ 12.09 (brs, 1H), 7.42-7.58 (m, 6H), 6.13(s, 1H), 5.75 (d, 1H, J=2.7 Hz), 5.03 (m, 1H), 4.74 (m, 1H), 4.19-4.40 (m, 3H) , 1.74 (m, 2H) , 1.48 (d, 3H, J=8.4 Hz), 1.29— 1.43 (m, 5H, J=6.3 Hz), 0.90(t, 3H, J=7.2 Hz); ESI- MS m/z (M+Na+) 470。
IIIc: NMR (300 MHz, CDC13): δ 12.05 (brs, 1H), 7.30-7.50 (m, 5H), 6.07 (s, 1H), 5.68 (m, 1H), 4.97—5.11 (m, 1H), 4.66 (m, 1H),4.17-4.44 (m, 3H) , 1.70 (m, 2H) , 1.48 (d, 3H, J=8.4 Hz), 1.20— 1.37 (m, 5H), 0.85 (t, 3H, J=7.2 Hz); ESI- MS m/z (M+Na+) 504。
Hid: NMR (300 MHz, CDC13): δ 12.03(brs, 1H), 7.31-7.51 (m, 11H), 5.80 (d, 1H, J=2.1 Hz), 4.90 (m, 1H), 4.55 (dd, 1H, J=6.9, 4.2 Hz), 4.45 (dd, 1H, J=5.4, 4.8 Hz), 4.01-4.18 (m, 2H) , 1.72 (m, 2H) , 1.40 (d, 3H, J=8.4 Hz) , 1.25-1.37 (m, 5H, J=6.3 Hz) , 0.90(t, 3H, J=7.2 Hz)。
1Mb lllc Mid
Example π:
dissolving 1.3 g of Ilia in 10 ml of ethanol, cooling to 0 ℃, stirring, slowly dropwise adding 10 ml of HCl/ethanol solution, keeping the reaction temperature at 0 ℃, removing the solvent under reduced pressure after 4 hours, dissolving the residue in dichloromethane, and dissolving the dichloromethane with saturated NaHC03The aqueous solution was washed, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 1.0 g of the product (capecitabine). NMR (300 MHz, d-DMSO): δ 8.03(brs, 1H), 5.67 (d, 1H, J =4.8 Hz), 4.08 (M, 3H), 3.90 (M, 1H), 3.68 (q, 1H, J =6.0 Hz), 1.60(M, 2H), 1.22-1.31 (M, 7H), 0.88 (t, 3H, J =6.4 Hz), ESI-MS M/z (M +) 358.
Ilia Capicetabine
Examples 18 to 20:
capecitabine was obtained in the same manner as in example 17 using IIIb, IIIc or Illd as starting materials, respectively.

Claims (28)

  1. Claims to follow
    1. A compound, a deoxyfluorouracil derivative, of formula (I):
    (I) Wherein ^ is selected from a hydrogen atom, a straight chain or branched alkyl group containing 1-8 carbon atoms, a benzene ring or a substituted benzene ring; r2OptionallyFrom a hydrogen atom, a straight or branched alkyl group containing 1 to 8 carbon atoms, a benzene ring or a substituted benzene ring.
  2. 2. A process for producing a deoxyfluorouracil derivative represented by the formula (I) according to claim 1, which comprises subjecting deoxyfluorouracil to condensation reaction with an aldehyde or ketone in the presence of an acidic catalyst to obtain a deoxyfluorouracil derivative represented by the formula (I).
  3. 3. A compound, deoxycytidine derivative, represented by formula (II):
    (Π), wherein ^ can be selected from hydrogen atom, alkyl, benzene ring or substituted benzene ring; r2Can be selected from hydrogen atom, alkyl, benzene ring or substituted benzene ring.
  4. 4. A process for producing a deoxycytidine derivative represented by the formula (II) according to claim 3, which comprises reacting a deoxycytidine derivative represented by the formula (I) with phosphorus oxychloride, an organic base and aqueous ammonia to obtain a deoxycytidine derivative represented by the formula (II).
  5. 5. A compound, deoxycytidine derivative, represented by formula (III):
    (III) wherein ^ can be selected from hydrogen atom, alkane: a cyclic or substituted benzene ring; r2Can be selected from hydrogen atom, alkyl, benzene ring or substituted benzene ring.
  6. 6. The process for producing a fluorocytidine derivative represented by the formula (III) according to claim 5, which comprises reacting a fluorocytidine derivative represented by the formula (II) with a compound represented by the formula (IV) to give a fluorocytidine derivative represented by the formula (in);
    (IV) ,
    r is a leaving group.
  7. 7. The method according to claim 6, wherein the compound of formula (IV) is preferably three of the following compounds:
  8. 8. the preparation method of capecitabine is characterized in that the hydroxyl protecting group of the deoxycytidine derivative shown as the formula (III) is removed under acidic conditions to obtain the capecitabine.
  9. 9. The process according to claim 8, wherein the deoxycytidine derivative of formula (III) is obtained by reacting a deoxycytidine derivative of formula (II) with a compound of formula (IV).
  10. 10. The process according to claim 9, wherein the deoxycytidine derivative of formula (II) is a deoxycytidine derivative of formula (I) with phosphorus oxychloride and an organic base
  11. 11. The preparation method according to claim 10, wherein the deoxyfluorouracil derivative represented by the formula (I) is obtained by condensation reaction of deoxyfluorouracil with an aldehyde or ketone in the presence of an acidic catalyst.
  12. 12. The method according to claim 11, wherein the condensation reaction of deoxyfluorouracil with an aldehyde or ketone is carried out in a solvent mixture of toluene, benzene, acetone, tetrahydrofuran, dichloromethane or dichloroethane, or a mixture thereof in any ratio, to which an acidic catalyst is added.
  13. 13. The process according to claim 2 or 12, wherein the acidic catalyst is selected from p-toluenesulfonic acid, zinc chloride and tin chloride.
  14. 14. The method of claim 12, wherein the reaction temperature of the reaction is from-20 ℃ to 120 ℃: .
  15. 15. The method of claim 14, wherein the reaction temperature of the reaction is 80 ℃ to 120 ℃.
  16. 16. The method according to claim 12, wherein the molar ratio of the deoxyfluorouracil to the aldehyde or ketone is from 1:1 to 1: 2.
  17. 17. The process according to claim 10, wherein the reaction of the desflurouracil derivative of formula (I) with phosphorus oxychloride, an organic base and aqueous ammonia is carried out in acetonitrile or other water-miscible aprotic solvent mixture.
  18. 18. The method of claim 17, wherein the reaction temperature is from-10 ℃ to 30 ℃.
  19. 19. The method of claim 18, wherein the reaction temperature is from-5 ℃ to 20 ℃.
  20. 20. The process according to claim 9, wherein the reaction between the deoxycytidine derivative of formula (II) and the acylating agent of formula (IV) is carried out in acetonitrile or other aprotic solvent to which a basic catalyst is added.
  21. 21. The method of claim 20, wherein the basic catalyst is an inorganic base or an organic base.
  22. 22. The method of claim 21, wherein the basic catalyst is selected from the group consisting of potassium carbonate, triethylamine, and pyridine.
  23. 23. The method of claim 22, wherein the reaction temperature of the reaction is from-10 ℃ to-50 ℃.
  24. 24. The method of claim 23, wherein the reaction is carried out at a reaction temperature of from 0 ℃ to 20 ℃: .
  25. 25. The process according to claim 24, wherein the molar ratio of the deoxycytidine derivative of formula (II) to the acylating agent of formula (IV) is 1:1.1 to 1: 3.
  26. 26. The process according to claim 25, wherein the molar ratio of the deoxycytidine derivative of formula (II) to the acylating agent of formula (IV) is 1:1.1 to 1: 2.
  27. 27. The process according to claim 8, wherein the reaction for deprotecting a deoxycytidine derivative represented by the formula (III) to obtain capecitabine is carried out in an aqueous solution of a protic acid, an alcoholic solution of a protic acid, an ethereal solution or a solution of an aprotic acid.
  28. 28. The process according to claim 27, wherein the deprotection of the deoxycytidine derivative represented by the formula (III) to obtain capecitabine is carried out in an alcohol solution of protonic acid.
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